IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS

WORKSHOP SUMMARY

National Cancer Policy Forum

Margie Patlak and Sharyl Nass, Rapporteurs

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
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National Cancer Policy Forum Margie Patlak and Sharyl Nass, Rapporteurs

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This study was supported by Contract Nos. HHSN261200611002C, 200-2005-13434 TO #1, HHSP233200700373P, and 223-01-2460 TO #27, between the National Acad- emy of Sciences and the National Cancer Institute, the Centers for Disease Control, the Agency for Healthcare Research and Quality, and the Food and Drug Administra- tion, respectively. This study was also supported by the American Cancer Society, the American Society for Clinical Oncology, C-Change and the Association of American Cancer Institutes. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-11668-8 International Standard Book Number-10: 0-309-11668-6 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2008 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2008. Improving the quality of cancer clinical trials: Workshop summary. Washington, DC: The National Academies Press.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a man- date that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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WORKSHOP PLANNING COMMITTEE JOHN MENDELSOHN, M.D. (Co-Chair), President, MD Anderson Cancer Center HAROLD MOSES, M.D. (Co-Chair), Professor of Molecular Oncology, Cancer Biology, Medicine, and Pathology; Director Emeritus, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center JAMES DOROSHOW, M.D., Director, Division of Cancer Treatment and Diagnosis, National Cancer Institute ROY HERBST, M.D., Ph.D., Professor and Chief, Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center HEDVIG HRICAK, M.D., Professor and Chair, Department of Radiology, Memorial Sloan-Kettering Cancer Center GILBERT OMENN, M.D., Ph.D., Professor, Internal Medicine, Human Genetics, and Public Health, University of Michigan Medical School DAVID PIWNICA-WORMS, M.D., Ph.D., Professor, Department of Radiology, Washington University School of Medicine JOHN WAGNER, M.D., Ph.D., Executive Director, Department of Clinical Pharmacology, Merck, Inc. JANET WOODCOCK, M.D., Deputy Commissioner and Chief Medical Officer, Food and Drug Administration IOM planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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NATIONAL CANCER POLICY FORUM HAROLD L. MOSES, M.D. (Chair), Professor of Molecular Oncology, Cancer Biology, Medicine, and Pathology; Director Emeritus, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center PETER BACH, M.D., M.A.P.P., Associate Attending Physician, Memorial Sloan-Kettering Cancer Center EDWARD BENZ, JR., M.D., President, Dana-Farber Cancer Center THOMAS BURISH, Ph.D., Past Chair, American Cancer Society Board of Directors, and Provost, Notre Dame University BETTY FERRELL, Ph.D., R.N., F.A.A.N., Research Scientist, City of Hope National Medical Center JOSEPH FRAUMENI, JR., M.D., Director, Division of Cancer Epidemiology and Genetics, National Cancer Institute STEPHEN FRIEND, M.D., Ph.D., Executive Vice President, Oncology, Merck, Inc. PATRICIA GANZ, M.D., American Society of Clinical Oncology, Board Member, and Professor of Medicine, University of California, Los Angeles ROBERT GERMAN, Dr.Ph., M.P.H., Associate Director for Aging, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention ROY HERBST, M.D., Professor and Chief, Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center THOMAS KEAN, M.P.H., Executive Director, C-Change WILLIAM LAWRENCE, M.D., M.S., Medical Director, Center for Outcomes and Evidence, Agency for Healthcare Research and Quality LYNN MATRISIAN, Ph.D., Professor and Chair, Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine JOHN NIEDERHUBER, M.D., Director, National Cancer Institute DAVID PARKINSON, M.D., Senior Vice President, Oncology Research and Development, Biogen IDEC EDITH PEREZ, M.D., Professor of Medicine and Director, Cancer Clinical Study Unit, Mayo Clinic SCOTT RAMSEY, M.D., Ph.D., Full Member, Fred Hutchinson Cancer Research Center vi

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MARGARET SPITZ, M.D., Chair of Epidemiology, MD Anderson Cancer Center ELLEN STOVALL, President and Chief Executive Officer, National Coalition for Cancer Survivorship BARRY STRAUBE, M.D., Director, Office of Clinical Standards and Quality, Centers for Medicare & Medicaid Services JANET WOODCOCK, M.D., Deputy Commissioner and Chief Medical Officer, Food and Drug Administration Staff SHARYL NASS, Ph.D., Study Director ROGER HERDMAN, M.D., Director, National Cancer Policy Forum LAURA LEVIT, J.D., Research Associate CHRISTINE MICHEEL, Ph.D., Christine Mirzayan Science and Technology Policy Graduate Fellow MICHAEL PARK, Senior Program Assistant ALEX REPACE, Senior Program Assistant MARGIE PATLAK, Science Writer IOM forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vii

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Ray DuBois, M.D., Ph.D., University of Texas MD Anderson Cancer Center Doug Hanahan, Ph.D., University of California, San Francisco Hedvig Hricak, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center Susan M. Jerian, M.D., OncoRD, Inc. Daniel C. Sullivan, M.D., Duke Cancer Center Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen ix

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x REVIEWERS by Melvin Worth, M.D. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authors and the institution.

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Contents Improving the Quality of Cancer Clinical Trials: Workshop Summary 1 Introduction, 1 New Clinical Trial Designs, 3 Phase 0 Trials, 3 Adaptive Trial Designs, 16 Targeting Multiple Pathways with Multiple Drugs, 23 Preclinical Model Systems, 36 Molecular Imaging, 40 Current and Developing Methods, 40 Challenges of Molecular Imaging, 46 Screening for Predictive Markers, 49 The Challenges of Clinical Validation, 50 Bioimaging Predictive Markers, 55 Clinical Translation, 59 Panel Discussion, 65 Costs of Clinical Trials, 67 Regulatory Costs, 68 Patient Accrual, 70 Global Outsourcing, 72 Time Is Money, 74 Public–Private Collaborations, 75 xi

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xii CONTENTS Regulatory Issues, 77 Regulatory Barriers to Innovation, 77 Patient Advocacy Perspective, 81 Regulation of In Vitro Diagnostics, 83 Regulatory Issues in Improving Cancer Clinical Trials, 86 Reports from the Case Study Discussion Groups, 89 Adaptive Trial Design, 89 Phase 0 Trials, 91 Imaging, 93 Use of Proteomics/Genomics to Assign Therapy in Lung Cancer, 96 Use of Genetics/Genomics to Assign Therapy, 98 Concluding Remarks, 101 References, 102 Acronyms 107 Glossary 109 Appendixes A Workshop Agenda 115 B Workshop Speakers, Moderators, and Invited Discussants 123